Abstract |
Several lines of circumstantial evidence support the assumption that protein kinase C (PKC) activation together with elevated levels of cytosolic Ca++ are necessary for T-cell activation and proliferation in response to a physiological stimulus, i.e., MHC class II restricted antigen presentation. By using a potent, cell-permeable and selective inhibitor of PKC, Ro 32-0432, we have tested this hypothesis. Ro 32-0432 inhibits interleukin-2 (IL-2) secretion, IL-2 receptor expression in, and proliferation of, peripheral human T-cells stimulated with phorbol ester together with phytohemagglutin or anti-CD3, but does not inhibit IL-2 induced proliferation in cells already stimulated to express IL-2 receptors. Proliferation of the influenza peptide antigen HA 307-319-specific human T-cell clone (HA27) after exposure to antigen-pulsed autologous presenting cells was also inhibited by Ro 32-0432. Oral administration of Ro 32-0432 inhibited subsequent phorbol ester-induced edema in rats demonstrating the systemic efficacy of the compound to inhibit PKC-driven responses. Induction of more physiologically T-cell driven responses such as host vs. graft responses and the secondary paw swelling in adjuvant-induced arthritis were also inhibited by Ro 32-0432. These data demonstrate the crucial role for PKC in T-cell activation and that selective p.o. bioavailable PKC inhibitors are efficacious in preventing T-cell driven chronic inflammatory responses in vivo. Inhibition of PKC represents an important mechanistic approach to prevent T-cell activation and compounds of this class may have important therapeutic applicability to chronic inflammatory and autoimmune diseases.
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Authors | A M Birchall, J Bishop, D Bradshaw, A Cline, J Coffey, L H Elliott, V M Gibson, A Greenham, T J Hallam, W Harris |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 268
Issue 2
Pg. 922-9
(Feb 1994)
ISSN: 0022-3565 [Print] United States |
PMID | 8114006
(Publication Type: Journal Article)
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Chemical References |
- Indoles
- Pyrroles
- Ro 32-0432
- Phorbol 12,13-Dibutyrate
- Protein Kinase C
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Topics |
- Administration, Oral
- Amino Acid Sequence
- Animals
- Arthritis, Experimental
(prevention & control)
- Female
- Indoles
(pharmacology)
- Lymphocyte Activation
(drug effects)
- Male
- Mice
- Molecular Sequence Data
- Phorbol 12,13-Dibutyrate
(pharmacology)
- Protein Kinase C
(antagonists & inhibitors)
- Pyrroles
(pharmacology)
- Rats
- Rats, Inbred Lew
- T-Lymphocytes
(drug effects, immunology)
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